Extracellular proteolysis plays a key role in a number of biological processes. Angiogenesis, wound healing, and inflammatory reactions all depend on enzymes which remodel connective tissues in the extracellular matrix. Tumor cell invasion and metastasis also requires proteolytic enzymes for their growth. The involvement of matrix metalloproteases (MMPs) and serine proteases (SPs) in extracellular degradation has been clearly demonstrated and the number of disease states that these enzymes impact on are many. Arthritis, multiple sclerosis, osteoporosis, Alzheimer's disease, cancer growth and metastasis, to name a few, all rely on these processes. Therefore, inhibition of these proteolytic enzymes is a useful approach to the treatment of various diseases. This synthesis project, as part of the overall center for protease studies, will address the following: 1) the synthesis of known MMP and SP inhibitors for center studies; 2) the synthesis of novel inhibitors of MMPs containing new zinc binding domains and new aminoacid backbones; 3) the development of a synthesis of naturally occurring molecules and analogs, which are SP inhibitors. Collaborative functions with the Center will include: 1) the supply of known and new inhibitors for biological screening assays (Sehgal), biopharmaceutics (QSTAR with Balaz), and model studies for targeting and delivery (Rodgers/Mallik); 2) the preparation of functional inhibitors for attachment to liposomes for drug delivery studies (with Rodger/Mallik group); 3) the incorporation of chromophores onto known MMP inhibitors for photodynamic therapy (with Rodger/Mallik group).